Market Overview

Approval of Linzess® Tablets 0.25 mg in Japan for Additional Indication of Chronic Constipation


Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa,
Ph.D., "Astellas" ) and Ironwood Pharmaceuticals, Inc (Nasdaq: IRWD ,
"Ironwood") today announced that approval has been obtained in Japan for
the guanylate cyclase-C receptor agonist "Linzess® Tablets
0.25 mg (generic name: linaclotide)" for the additional indication of
chronic constipation (other than constipation associated with organic
disorders1) ("chronic constipation").

Linzess® Tablets 0.25 mg were licensed from Ironwood and
have been developed and commercialized in Japan by Astellas. It was
approved in Japan in December 2016 for the indication of irritable bowel
syndrome with constipation (IBS-C)2, and has been on the
Japanese market since March 2017.

This approval is based on the results of a Phase 3, double-blind,
placebo-controlled, parallel group trial conducted to evaluate the
efficacy and safety of linaclotide orally administered for 4 weeks in
186 Japanese patients with chronic constipation. The subjects were
randomly assigned to either the linaclotide (0.5 mg) or placebo group in
a 1:1 ratio. In the linaclotide group, the change in weekly mean
frequency of spontaneous bowel movement (SBM)3 at 1 week
after the start of administration, which was the primary endpoint,
represented a statistically significant improvement as compared to the
placebo group. The most common adverse event was diarrhea, and its
severity was mild to moderate in all cases.

Constipation is defined as the state in which feces cannot be
excreted adequately and comfortably4, and it is classified as
chronic or transient condition depending on its duration5.
The prevalence of constipation in Japan has been reported as 2.5% for
men and 4.6% for women6.

By providing a new therapy option with the additional chronic
constipation indication, Astellas and Ironwood hope to be able to make a
significant contribution to a large number of patients suffering from
chronic constipation.

The impact of the approval of the additional chronic constipation
indication has already been factored into Astellas' consolidated
financial forecast for the fiscal year ending March 2019.

(1) Organic disorders: Disorders caused by the
anatomical/pathological changes or abnormalities in the visceral,
organic, nervous, or other tissues (detectable by examinations such as
radiography and endoscopy).

(2) Irritable bowel syndrome constipation (IBS-C): A condition
associated with irritable bowel syndrome (IBS) in which hard or lumpy
stool constitute 25% or more and soft (mushy) or watery stools
constitute less than 25% of feces. IBS is a functional disorder
characterized by the absence of organic disorders and by its main
gastrointestinal manifestations of abdominal pain/discomfort and
abnormal bowel movement (diarrhea, constipation) that persist for a long
time or relapse over time. The abnormal bowel movement and the abdominal
symptoms associated with IBS are induced by various factors, including
stress, that excessively activate the enteric nerves and eventually
cause gastrointestinal hypermotility.

(3) Spontaneous bowel movement (SBM): A bowel movement occurring
without treatments (the use of a laxative, suppository, or enema,
disimpaction, etc.) on the same or the previous day.

(4) Clinical Guidelines for Chronic Constipation 2017: Edited by Japan
Society of Gastroneterology-affiliated Study Group, Chronic Constipation
Diagnosis and Treatment Study Group; Nankodo. p.2

(5) Clinical Guidelines for Pediatric Chronic Functional Constipation:
Edited by Japanese Society for Pediatric Gastroenterology, Hepatology
and Nutrition; Japan Pediatric Gastrointestinal Function Study Group;
SHINDAN TO CHIRYO SHA (Diagnosis and Treatment Inc.). p. 14

(6) Ministry of Health, Labour and Welfare: Comprehensive Survey of
Living Conditions (2016). p. 29


Revisions to the package insert with the approval of the additional
indication are shown below.

After revision (addition underlined)   Before revision

Irritable bowel syndrome with constipation

Chronic constipation (other than constipation associated
with organic disorders)


Irritable bowel syndrome with



About Linaclotide
Linaclotide is a guanylate cyclase‐C
(GC‐C) agonist that is thought to work in two ways based on nonclinical
studies. Linaclotide binds to the GC-C receptor locally, within the
intestinal epithelium. Activation of GC-C results in increased
intestinal fluid secretion and accelerated transit and a decrease in the
activity of pain-sensing nerves in the intestine. The clinical relevance
of the effect on pain fibers, which is based on nonclinical studies, has
not been established. Linaclotide is marketed by Ironwood and Allergan
plc in the United States as LINZESS® and is
indicated for the treatment of adults with irritable bowel syndrome with
constipation (IBS-C) or chronic idiopathic constipation (CIC), with
nearly 2 million unique patients in the United States having filled
nearly 11 million linaclotide prescriptions since launch, according
to IQVIA. Linaclotide is marketed by Allergan for the treatment of
adults with moderate to severe IBS-C in Europe under the brand
name CONSTELLA®. Astellas has the exclusive rights to
develop and commercialize linaclotide in Japan based on the license
agreement with Ironwood from 2009. Ironwood also has partnered with
AstraZeneca for development and commercialization of linaclotide
in China, Hong Kong and Macau.

About Astellas
Astellas Pharma Inc., based in Tokyo, Japan,
is a company dedicated to improving the health of people around the
world through the provision of innovative and reliable pharmaceutical
products. For more information, please visit our website at

Astellas Cautionary Notes
In this press release, statements
made with respect to current plans, estimates, strategies and beliefs
and other statements that are not historical facts are forward-looking
statements about the future performance of Astellas. These statements
are based on management's current assumptions and beliefs in light of
the information currently available to it and involve known and unknown
risks and uncertainties. A number of factors could cause actual results
to differ materially from those discussed in the forward-looking
statements. Such factors include, but are not limited to: (i) changes in
general economic conditions and in laws and regulations, relating to
pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii)
delays in new product launches, (iv) the inability of Astellas to market
existing and new products effectively, (v) the inability of Astellas to
continue to effectively research and develop products accepted by
customers in highly competitive markets, and (vi) infringements of
Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently
in development) which is included in this press release is not intended
to constitute an advertisement or medical advice.

About Ironwood
Ironwood Pharmaceuticals (NASDAQ:IRWD) is a
commercial biotechnology company focused on creating medicines that make
a difference for patients, building value for our fellow shareholders,
and empowering our passionate team. We are currently commercializing two
innovative primary care products: linaclotide, the U.S. branded
prescription market leader for adults with irritable bowel syndrome with
constipation (IBS-C) or chronic idiopathic constipation (CIC), and
lesinurad, which is approved to be taken with a xanthine oxidase
inhibitor (XOI), or as a fixed-dose combination with allopurinol, for
the treatment of hyperuricemia associated with gout. We are also
advancing a pipeline of innovative product candidates in areas of
significant unmet need, including persistent gastroesophageal reflux
disease, diabetic nephropathy, heart failure with preserved ejection
fraction, achalasia and sickle cell disease. Ironwood was founded in
1998 and is headquartered in Cambridge, Mass. For more information,
please visit
information that may be important to investors will be routinely
posted in both these locations.

Ironwood Cautionary Notes
This press release contains
forward-looking statements. Investors are cautioned not to place undue
reliance on these forward-looking statements, including statements about
the development, launch, commercial availability and commercial
potential of linaclotide, the potential indications for, and benefits
of, linaclotide; and the anticipated timing of preclinical, clinical and
regulatory developments and the design, timing and results of clinical
and preclinical studies. Each forward‐looking statement is subject to
risks and uncertainties that could cause actual results to differ
materially from those expressed or implied in such statement. Applicable
risks and uncertainties include those related to preclinical and
clinical development, manufacturing and formulation development; the
effectiveness of development and commercialization efforts by us and our
partners; the risk that findings from our completed nonclinical and
clinical studies may not be replicated in later studies; efficacy,
safety and tolerability of linaclotide; decisions by regulatory and
judicial authorities; the risk that we or our partners may never get
sufficient patent protection for linaclotide or that we or they are not
able to successfully protect such patents; the outcomes in legal
proceedings to protect or enforce the patents relating to linaclotide;
developments in the intellectual property landscape; challenges from and
rights of competitors or potential competitors; the risk that our
planned investments do not have the anticipated effect on our company
revenues, products or product candidates; the risk that we are unable to
manage our operating expenses or cash use for operations, or are unable
to commercialize our products, within the guided ranges or otherwise as
expected; and the risks listed under the heading "Risk Factors" and
elsewhere in Ironwood's Quarterly Report on Form 10-Q for the quarter
ended June 30, 2018, and in our subsequent SEC filings. These
forward-looking statements (except as otherwise noted) speak only as of
the date of this press release, and Ironwood undertakes no obligation to
update these forward-looking statements.

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